The urokinase plasminogen activator (uPA) is an extracellular serine protease. UPA consists of 3 domains: 1) The growth factor domain (GFD) that mediates binding of uPA to its receptor uPAR; 2) The kringle domain of uPA that is described to interact with integrins; and 3) The catalytic domain that mediates the proteolytic function of uPA. The primary proteolytic function of uPA is to convert the inactive zymogen plasminogen (Plg) to the active serine protease plasmin. UPA is produced as a single-chain zymogen (sc-uPA), which can be endoproteolytically cleaved at the Lys158-Ile159 peptide bond (numbering corresponding to human sc-uPA). The resulting two-chain form of uPA (tc-uPA) is held together by a single disulfide bridge. The proteolytic activity of sc-uPA is minimal compared to that of tc-uPA, but sc-uPA does harbour some intrinsic proteolytic activity. The catalytic domain of uPA exists in equilibrium of two structural conformations, an active and an inactive conformation. In sc-uPA the inactive conformation of the catalytic domain is favoured. Hydrolysis of the Lys158-Ile159 peptide bond shifts the dynamic equilibrium between these structural conformations to favour the active form (Jiang et al., Biochem. J. 449:161-166, 2013).
In the healthy organism, the presence of uPA outside the urinary and gastrointestinal tract is generally limited to circulating granulocytes and certain cell types in tissues undergoing remodelling. During disease, uPA is also found at sites of inflammatory disorders and cancer lesions. Animal studies have demonstrated a functional role of uPA in cancer and in inflammatory disorders including arthritic diseases. Antagonising uPA would therefore be desirable in treatment of cancer and inflammatory diseases such as rheumatoid arthritis and psoriatic arthritis.
Patent documents U.S. Pat. No. 8,062,637 and WO03033009 provide experimental evidence for a functional role of uPA in arthritic diseases. The documents further describe a method for ameliorating the effects of an inflammatory disease in a subject, comprising administering to the subject an antagonist, including antibodies that specifically bind uPA. The documents U.S. Pat. No. 8,062,637 and WO03033009 describe possible uses of antibodies that bind uPA but neither of the documents describe or provide data for any antibody that binds uPA.
Patent document WO2006050177 describes a method for identifying anti-uPA antibodies that are specific for an 86 amino acid long epitope corresponding to the kringle domain of uPA and the potential use of these antibodies for treatment of inflammatory diseases. The WO2006050177 patent document does not describe or provide data for any antibody that binds uPA. Furthermore, antibodies that bind to the kringle domain are predicted to have no effect on the proteolytic function of uPA, because the proteolytic properties of uPA are primarily associated with the catalytic domain.
Patent document WO2005048822 describes two anti-uPA antibodies, ATN-291 and ATN-292, that specifically bind to the growth factor domain (GFD) (ATN-292) and the kringle domain (ATN-291) of uPA. The WO2005048822 patent document further describes the potential use of these antibodies for treatment of cancer or other diseases. Antibodies that bind to either the GFD or the kringle domain are predicted to have no effect on the proteolytic function of uPA, because the proteolytic properties of uPA are primarily associated with the catalytic domain.
Patent document U.S. Pat. No. 5,496,549 describes a bispecific antibody, in which one of the two specificities is conferred by either of three anti-uPA antibodies, UK1-3, UK1-87, and UK1-6. The other specificity is towards a platelet surface protein and the patent further describes the potential use of these bispecific antibodies to deliver an active biological substance, in this case uPA, for treatment of thrombosis or other cardiovascular disease. None of these three antibodies inhibit the proteolytic activity of uPA but are designed to deliver or concentrate uPA at sites of platelet deposition.
As described above, antibodies that bind uPA are known; and their uses in treatment of inflammatory diseases have been envisaged. However to current date, no anti-uPA antibodies have entered clinical trials. Thus, there is still an unmet need for therapeutic anti-uPA antibodies for example for use in patients with inflammatory diseases or patients with cancer.
Disclosed herein are anti-uPA antibodies with novel characteristics. These antibodies are suitable for the development of pharmaceuticals. Such antibodies may have a substantial impact upon the quality of life of individuals with cancer or inflammatory diseases.